Dissociation Rate Research Articles

Master equation modeling of blackbody infrared radiative dissociation (BIRD) of hydrated peroxycarbonate radical anions.

Molecular cluster ions, which are stored in an electromagnetic trap under ultra-high vacuum conditions, undergo blackbody infrared radiative dissociation (BIRD). This process can be simulated with master equation modeling (MEM), predicting temperature-dependent dissociation rate constants, which are very sensitive to the dissociation energy. We have recently introduced a multiple-well approach for master equation modeling, where several low-lying isomers are taken into account. Here, we experimentally measure the BIRD of CO4●-(H2O)1,2 and model the results with a slightly modified multiple-well MEM. In the experiment, we exclusively observe loss of water from CO4●-(H2O), while the BIRD of CO4●-(H2O)2 leads predominantly to loss of carbon dioxide, with water loss occurring to a lesser extent. The MEM of two competing reactions requires empirical scaling factors for infrared intensities and the sum of states of the loose transition states employed in the calculation of unimolecular rate constants so that the simulated branching ratio matches the experiment. The experimentally derived binding energies are ΔH0(CO4●--H2O) = 45 ± 3kJ/mol, ΔH0(CO4●-(H2O)-H2O) = 41 ± 3kJ/mol, and ΔH0(CO2-O2●-(H2O)2) = 37 ± 3kJ/mol. Quantum chemical calculations on the CCSD(T)/aug-cc-pVTZ//CCSD/aug-cc-pVDZ level, corrected for the basis set superposition error, yield binding energies that are 2-5kJ/mol higher than experiment, within error limits of both experiment and theory. The relative activation energies for the two competing loss channels are as well fully consistent with theory.

Accurate Characterization of Binding Kinetics and Allosteric Mechanisms for the HSP90 Chaperone Inhibitors Using AI-Augmented Integrative Biophysical Studies

Accurate Characterization of Binding Kinetics and Allosteric Mechanisms for the HSP90 Chaperone Inhibitors Using AI-Augmented Integrative Biophysical Studies

Decreasing exciton dissociation rates for reduced voltage losses in organic solar cells

Enhancing the device electroluminescence quantum efficiency (EQEEL) is a critical factor in mitigating non-radiative voltage losses (VNR) and further improving the performance of organic solar cells (OSCs). While the common understanding attributes EQEEL in OSCs to the dynamics of charge transfer (CT) states, persistent efforts to manipulate these decay dynamics have yielded limited results, with the EQEEL of high-efficiency OSCs typically remaining below 10−2%. This value is considerably lower than that observed in high efficiency inorganic photovoltaic devices. Here, we report that EQEEL is also influenced by the dissociation rate constant of singlet states (kDS). Importantly, in contrast to the traditional belief that advocates maximizing kDS for superior photovoltaic quantum efficiency (EQEPV), a controlled reduction in kDS is shown to enhance EQEEL without compromising EQEPV. Consequently, a promising experimental approach to address the VNR challenge is proposed, resulting in a significant improvement in the performance of OSCs.

Functional insights of Tyr37 in framework region 2 directly contributing to the binding affinities and dissociation kinetics in single-domain VHH antibodies

Single-domain VHH antibody is regarded as one of the promising antibody classes for therapeutic and diagnostic applications. VHH antibodies have amino acids in framework region 2 that are distinct from those in conventional antibodies, such as the Val37Phe/Tyr (V37F/Y) substitution. Correlations between the residue type at position 37 and the conformation of the CDR3 in VHH antigen recognition have been previously reported. However, few studies focused on the meaning of harboring two residue types in position 37 of VHH antibodies, and the concrete roles of Y37 have been little to be elucidated. Here, we investigated the functional states of position 37 in co-crystal structures and performed analyses of three model antibodies with either F or Y at position 37. Our analysis indicates that Y at position 37 enhances the dissociation rate, which is highly correlated with drug efficacy. Our findings help to explain the molecular mechanisms that distinguish VHH antibodies from conventional antibodies.

Pore-scale visualization of hydrate dissociation and mass transfer during depressurization using microfluidic experiments

Natural gas hydrate is a potential low-carbon energy resource. Extracting this resource efficiently remains a challenge, due to the intricacies involved in multiphase reactive transport during hydrate dissociation. This study employs microfluidic experimental techniques to observe pore-scale interactions during depressurization-induced hydrate dissociation, utilizing high-resolution spatial and temporal imagery. Supervised machine learning algorithms segmented these microscopic images, enabling the analysis of phase saturation changes and hydrate dissociation rates. The study identifies two distinct hydrate forms in microfluidic chips: hydrate films and crystals, each exhibiting unique dissociation characteristics. Hydrate films decomposed rapidly in response to pressure reductions below equilibrium with the dissociation rate of O(10−1 %/s) under stationary gas–water conditions. When considering gas–water migration, the gas encapsulated in the hydrate film will be displaced by water, leading to a reduced dissociation rate. The hydrate crystal dissociation is much slower with the dissociation rate of O(10−3 %/s) under stationary gas–water conditions compared to the hydrate film, hindered by mass transfer limitations. Gas-water migration can enhance crystal dissociation. The formation and expansion of gas microbubbles under depressurization accelerated hydrate dissociation within a confined temporal and spatial range, which was known as the self-promotion mechanisms. Significantly, depressurization-induced gas slug flow increases the dissociation rate by more than one order of magnitude, compared to that in stationary gas–water conditions. The depressurization process played a significant role, not only by facilitating thermodynamic feasibility for hydrate dissociation but also by inducing the critical gas slug flow. These results of the present study provide theoretical guidance for improving natural gas hydrate production efficiency.

Dissociative Electron Transfer to N‐(Arylthio)phthalimides: Factors Affecting the Formation and Dissociation of Radical Anions

AbstractA series of chemically and biologically relevant N‐(arylthio)phthalimides is synthesized and its electrochemical reduction investigated. The results of the electrochemical study are analysed through application of Savéant's dissociative electron transfer theory and with the assistance of theoretical calculations. Reduction of all investigated N‐(arylthio)phthalimides leads to the corresponding radical anions, followed by the ejection of the phthalimide anion resulting from the dissociation of the N−S chemical bond. This stepwise electron transfer mechanism is evidenced by the electrochemical data which allow determination of the standard reduction potentials of all compounds. In the formation of the N‐(arylthio)phthalimide radical anions, the theoretical calculations show that the incoming electron, is hosted by the phthalimidyl group indicating a homolytic dissociation mechanism. The dissociation rate constants of the radical anions are deduced and show that upon changing the substituent from the MeO, to Me, H, F, Cl and Br the dissociation becomes faster. A good correlation with the Hammett substituent constants is also obtained. Application of Savéant's theory through determination of the associated driving force and the intrinsic barrier energies help rationalize the observed results and show that the change in the dissociation rate constant depends mainly on the standard reduction potential of the parent compounds.

Abstract 7141: The novel microtubule-destabilizing compound AUS_001 maintains unique binding to the colchicine site of tubulin and elicits reversible cellular effects relative to other anti-tubulin agents

Abstract Our previous work showed that the prenylated hydroxy-stilbene AUS_001 exerts a strong safety profile and potent anti-proliferative responses, as assessed in 30 types of cancer cell lines, stemming from its microtubule destabilization activity. The aim of the current study was to delineate the molecular mechanism of microtubule destabilization by AUS_001 and to provide insight into its high potency and low toxicity. Surface plasmon resonance (SPR) experiments revealed the direct interaction of AUS_001 with tubulin with an apparent equilibrium dissociation constant, Kd, of 2.13 × 10−5M. Size exclusion competition assays and an X-ray crystal structure of the tubulin-AUS_001 complex at 2.1 Å resolution establish ligand binding within the colchicine site on tubulin. Since colchicine-site ligands are well known to inhibit the curved-to-straight conformational transition of tubulin, which is an essential process for microtubule formation, these results readily explain the microtubule-destabilizing activity of the compound. Notably, while both combretastatin A4 (CA-4) and AUS_001 are both colchicine-site stilbene ligands, CA-4 binds in the cis configuration, while AUS_001 maintains a trans configuration leading to a substantially different pocket engagement. Comparison of the tubulin-AUS_001 complex structure with the ones of tubulin-colchicine and tubulin-plinabulin revealed that AUS_001 elicits different rearrangements in the T7 loop of β-tubulin versus colchicine and occupies a different zone of the pocket relative to plinabulin, further elaborating its unique binding properties. Interestingly, AUS_001 exhibits a higher relative affinity than colchicine itself, as assessed by i) an ultrafiltration-based tubulin-ligand release assay and ii) a radioligand colchicine competition assay. However, fitting steady state SPR data for AUS_001 binding to tubulin revealed fast association and dissociation rates and was indicative of reversible binding. The latter finding is corroborated by AUS_001-triggered reverse biological effects including morphological alterations, cell cycle G2/M arrest, and by a decrease of cell viability upon discontinuation of the drug treatment in glioma and pancreatic cancer cells. Conversely, colchicine, CA-4 or paclitaxel administered at the same doses as those applied for AUS_001 failed to reverse the drug-induced phenotypes upon removal resulting in sustained cytotoxicity. In conclusion, we fully characterized the unique binding mode of AUS_001 to the colchicine site of tubulin and elucidated the reversible nature of the target engagement. AUS_001 features a distinctive and reversible molecular interaction with tubulin which provides a plausible explanation for its favorable safety profile compared to other microtubule targeting agents. Citation Format: Herman Lelie, Yao-Chieh Chou, Alastair J. King, Zlata Boiarska, Andrea E. Prota, Michel O. Steinmetz, Marina Koutsioumpa. The novel microtubule-destabilizing compound AUS_001 maintains unique binding to the colchicine site of tubulin and elicits reversible cellular effects relative to other anti-tubulin agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7141.

Abstract 4388: Tumor-associated RhoA mutants interact with effectors in both GDP- and GTP-bound states

Abstract RhoA is the founding member of the Ras-homology (Rho) small GTPase family and is a master regulator for multiple cell functions. Recurrent RhoA mutations have been identified in several human cancers, particularly in leukemia/lymphoma and gastric cancer. Intriguingly, both gain-of-function and loss-of-function mutations of RhoA are present, suggesting that RhoA GTPase may have a more sophisticated role in cancer and requires more rigorous investigations. Here, we have focused on two of the gain-of-function RhoA mutations identified in Adult T cell Leukemia/lymphoma (ATLL) at residue A161 (A161P and A161V) and aim to reveal the underlying mechanistic basis for their function by biochemical and structural analyses. We found that in contrast to conventional gain-of-function RhoA mutants such as RhoAG14V and RhoAQ63L which affect the GTP-hydrolysis activity, RhoAA161P and RhoAA161Vare both fast-cycling with drastically increased nucleotide dissociation and association rates, but only slightly reduced GTP-hydrolysis activity. We solved the crystal structures of GDP-bound RhoAA161P and RhoAA161V and saw that while RhoAA161P displays impaired solvent-mediated interactions to the bound nucleotide, RhoAA161V has a more exposed nucleotide binding pocket compared to RhoAWT and RhoAA161P. Interestingly, RhoAA161P and RhoAA161Vcan interact with effector targets in the GDP-bound states. Further 1H-15N HSQC NMR study provides evidence of the active population in GDP-bound RhoAA161V. Molecule dynamics (MD) simulations show that the dynamic properties of RhoA switch regions are affected differently by the two mutations. Thus, RhoAA161V and RhoAA161P are fast-cycling mutants with distinct mechanisms, and both likely endow their GDP-bound state towards an active conformation. These findings provide a better understanding of the oncogenic role of RhoA mutations in cancer and shine light on how changes in RhoA protein dynamic properties caused by mutations may affect its function. Citation Format: Yuan Lin, Theresa A. Ramelot, Simge Senyuz, Attila Gursoy, Hyunbum Jang, Ruth Nussinov, Ozlem Keskin, Yi Zheng. Tumor-associated RhoA mutants interact with effectors in both GDP- and GTP-bound states [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4388.

Abstract 660: OPN-6602, a potent dual EP300/CBP bromodomain inhibitor, targets multiple myeloma through concomitant suppression of IRF4 and c-MYC

Abstract Multiple myeloma (MM) is an aggressive hematological cancer derived from malignant plasma cells in the bone marrow. E1A-binding protein (EP300) and CREB-binding protein (CBP) are transcription coactivators that contain both epigenetic writer histone acetyltransferase (HAT) and reader bromo- (BRD) domains that regulate transcription of genes via chromatin remodeling. EP300/CBP inhibition causes cell cycle arrest and apoptosis in MM through suppression of interferon regulatory factor (IRF4) and concomitant repression of c-MYC, rendering EP300/CBP as a novel target for MM. OPN-6602 is a potent, selective, and orally active small molecule dual EP300/CBP inhibitor discovered through structure guided drug design. Its binding interaction exhibits low nM activity on EP300 (Kd= 1.5 nM) and CREBBP (Kd= 1 nM), with > 200-fold less activity against BRD4. OPN-6602 binding to EP300 is particularly potent by Surface Plasmon Resonance analysis, displaying a Kd of 0.87 nM, with a fast association rate (1.5 E+06/Ms) and a slow dissociation rate (1.3 E-03/s) with a residence time of 13 min. It potently inhibits cell growth in MM cell lines OPM-2 (IC50 ~ 4 nM) and MM.1S (IC50 ~ 47 nM) as well as histone acetylation (IC50 ~ 2 nM) via BRD intramolecular modulation of HAT activity. OPN-6602 demonstrated potent inhibition of H3K27Ac in both LK2 (CBP-deficient lung cancer cells, IC50 = 11 nM) and in OPM-2 (IC50 = 1.6 nM). OPN-6602 also potently inhibited H3K27ac expression in PBMCs with IC50s of 0.75 and 1.4 nM, respectively. The effects of OPN-6602 with dexamethasone (dex) or lenalidomide (len) on the growth of OPM-2 and MM1.S cells were evaluated in a matrix combination study. As single agents, maximal growth inhibition reached 60-75% following dex treatment and only 30-40% following len treatment. In vitro combination studies utilizing a systematic assessment of a broad range of OPN-6602 concentrations in combination with dex or len demonstrated strong synergy. Synergy was observed between OPN-6602 at 3.7 nM and len through a concentration range from 0.027 to 20 µM. Synergy was observed with 1.2 or 3.7 nM of OPN-6602 in combo with dex concentrations from 0.055 to 40 µM. In the OPM-2 xenograft model, OPN-6602 inhibits tumor growth by 30-111% at doses from 2.5-60 mg/kg QD. This growth inhibition correlated with downregulation of IRF4 and cMYC in tumor samples analyzed by QPCR analysis. The pharmacokinetic profile is favorable for oral QD dose administration due to a high Cmax (19 µg/mL at 24 mg/kg) and short half-life (T1/2 = 1.5 hr). A first-in-human study of OPN-6602 in patients with MM is planned for 2024. Citation Format: Bernice Matusow, Wayne Spevak, Chao Zhang, Yan Ma, Rafe Shellooe, James Tsai, Pei Pei Li, Pan Yu Chen, Gaston Habets, Christine Nichols, Parmveer Singh, Kerry Inokuchi, Jackie Walling, Jason Halladay, Gideon Bollag. OPN-6602, a potent dual EP300/CBP bromodomain inhibitor, targets multiple myeloma through concomitant suppression of IRF4 and c-MYC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 660.

Abstract 6318: Development of an anti-PD-L1 CAR T therapeutic treating advanced gastric cancer with enhanced efficacy and lower off-tumor activities

Abstract Purpose: Driven by a relentless unmet need with unsatisfied cancer therapy, we aimed to develop chimeric antigen receptor T-cell (CAR-T) therapy for targeting advanced gastric cancer (AGC) expressing PD-L1. We constructed a 2nd generation CAR lentiviral vector expressing a unique anti-PD-L1 scFv with moderate affinity (VaxCAR001) in order to compare scFvs derived from Avelumab or Atezolizumab. This project focused on the efficacy and safety of PD-L1 CAR-Ts, which are affected by their binding affinity and dissociation with the target protein, PD-L1 during the treatment period. Methods and Results: The findings of this study revealed significant differences among PD-L1-targeting CAR-T cells with different affinities and dissociations. VaxCAR001 cells, showing intermediate affinity, demonstrated a higher CD8 ratio (up to 78% compared to 58% in Avelumab-derived and 45% in Atezolizumab-derived CAR-T), reduced expression of inhibitory markers including Tim-3, LAG-3, and TIGIT, (8%, 39% and 13% in VaxCAR001 vs 35%, 55% and 42 % in Avelumab, 19%, 51% and 34% in Atezolizumab scFv-derived CAR-T, respectively) and more sustained cytotoxicity. Notably, it maintained strong cytotoxicity even one month after production, while the Avelumab or Atezolizumab ScFv-derived CAR-T cells did not. In multicellular spheroid 3D co-culture with CAR T cells, VaxCAR001 exhibited superior infiltration into the core of spheroid and induced higher CAR-T-mediated killing for 3D tumor spheroids as indicated by LDH assay (68%, 800% increased than Avelumab or Atezolizumab scFv-derived CAR-T). Moreover, in an MSI-high AGC mouse model, treatment with VaxCAR001 cells resulted in a significant reduction in tumor size and prolonged survival until the end of the study period. On the other hand, treatment with the Avelumab or Atezolizumab scFv-derived CAR-T cells led to high mortality, with most mice succumbing within three weeks after CAR-T cell injection, suggesting an on-target off-tumor effect. Conclusion: This study demonstrates that VaxCAR001 cells bearing intermediate affinity and high dissociation rate for target PD-L1 showed the superior killing of PD-L expressing tumor cells in vitro and in vivo and manifested better safety profiles, as compared to CAR-T cells bearing scFv derived from commercial anti-PD-L1 targeting monoclonal antibodies such as avelumab and atezolizumab. VaxCAR001 revealed extended cytotoxicity, enhanced infiltration into tumor spheroids, and greater tumor size reduction in in vivo models. Importantly, it also demonstrated superior safety profiles, as evidenced by reduced expression of inhibitory markers and fewer off-tumor adverse effects. These findings would accelerate the clinical stage developments as an effective and safer treatment strategy against AGC. Citation Format: Minwoo Baek, Jae-In Yu, Eun-Ji Choi, Yeojin Lim, Jiwon Yang, Se-Ryeong Choi, Yoonjoo Choi, Mihwa Kim, Joon Haeng Rhee, Je-Jung Lee. Development of an anti-PD-L1 CAR T therapeutic treating advanced gastric cancer with enhanced efficacy and lower off-tumor activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6318.

Abstract 3109: Development of novel mono and bivalent nanobodies against EGFR for targeted cancer therapy

Abstract Introduction: The epidermal growth factor receptor (EGFR) plays a central role in the tumorigenesis of various solid tumors, rendering it a noteworthy target for cancer therapy. Nanobodies (Nbs) offer an appealing therapeutic approach due to their low immunogenicity, rapid clearance, and high targeting specificity. The aim of this study is to isolate, design, and characterize Nbs directed against EGFR. Methods: The Nb library was constructed following llama immunization with cells overexpressing EGFR. After three rounds of panning the phage-display library (both in solid phase and solution), individual clones were screened for EGFR reactivity using ELISA against Virus-Like Particles. Positive clones were sequenced, cloned into an expression vector, and then purified by immobilized metal affinity chromatography (IMAC). The Nbs were characterized through immunofluorescence (IF), flow cytometry (FACS), and surface plasmon resonance (SPR). The most promising candidates were used to design bivalent constructs, which were subsequently characterized by SPR and in a cell proliferation assay. Results: We successfully constructed an EGFR-targeted Nb library, which allowed the selection of multiple EGFR-specific Nbs following the optimization of the panning strategy. Two of the candidates exhibit strong binding to native EGFR in cells and outperform the gold standard anti-EGFR Nb 7D12. They demonstrate enhanced binding parameters in surface plasmon resonance (SPR) assays, with fast association and slow dissociation rates. The homo/heterodimeric bivalent constructs show improved affinity and the ability to inhibit cancer cell proliferation. Conclusion: We were able to develop novel mono and bivalent nanobodies with enhanced binding properties which can be used for targeted cancer therapy. Citation Format: Diana C. Aguilar Cortes, Mauro O. Heitrich, Marisa M. Fernandez, Santiago Werbajh, Gabriela Canziani, Vanesa Zylberman, Emilio L. Malchiod, Osvaldo L. Podhajcer, Sabrina E. Vinzón. Development of novel mono and bivalent nanobodies against EGFR for targeted cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3109.

Impact of the transport of magnetospheric electrons on the composition of the Triton atmosphere

Due to its inclined orbit and the complex geometry of the magnetic field of Neptune, Triton experiences a highly variable magnetic environment. As precipitation of magnetospheric electrons is thought to have a large impact on the Triton atmosphere, a better understanding of the interaction between its atmosphere and the magnetosphere of Neptune is important. We aim to couple a model of the Triton atmosphere with an electron transport model to compute the impact of a varying electron precipitation on the atmospheric composition. We coupled a recent photochemical model of the Triton atmosphere with the electron transport model TRANSPlanets. The inputs of this code were determined from Voyager 2 observations and previous studies. The main inputs were the electron precipitation flux, the orbital scaling factor, and the magnetic field strength. The electron-impact ionization and electron-impact dissociation rates computed by TRANSPlanets were then used in the photochemical model. We also analyzed the model uncertainties. The coupling of the two models enabled us to find an electron density profile, as well as N$_2$ and N number densities, that are consistent with the Voyager 2 observations. We found that photoionization and electron-impact ionization are of the same order, in contrast to the results of previous photochemical models. However, we emphasize that this result depends on the hypotheses we used to determine the input variables of TRANSPlanets. Our model would greatly benefit from new measurements of the magnetic environment of Triton, as well as of the electron fluxes in the Neptune magnetosphere.

From Molecular Dynamics to Taste Sensory Perception: A Comprehensive Study on the Interaction of Umami Peptides with the T1R1/T1R3-VFT Receptor.

The research on the umami receptor-ligand interaction is crucial for understanding umami perception. This study integrated molecular simulations, sensory evaluation, and biosensor technology to analyze the interaction between umami peptides and the umami receptor T1R1/T1R3-VFT. Molecular dynamics simulations were used to investigate the dissociation process of seven umami peptides with the umami receptor T1R1/T1R3-VFT, and by calculating the potential mean force curve using the Jarzynski equation, it was found that the binding free energy of umami peptide is between -58.80 and -12.17 kcal/mol, which had a strong correlation with the umami intensity obtained by time intensity sensory evaluation. Through correlation analysis, the dissociation rate constants (0.0126-0.394 1/s) of umami peptides were found to have a great impact on umami perception. The faster the dissociation rate of umami peptides from receptors, the stronger the perceived intensity of the umami taste. This research aims to elucidate the relationship between the umami peptide-receptor interaction and umami perception, providing theoretical support for the exploration of umami perception mechanisms.

Clinical Pharmacokinetics and Pharmacodynamics of Naloxone.

Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the μ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4-2 mg. Naloxone is rapidly eliminated [half-life (t1/2) 60-120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration (Tmax) 15-30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4-0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention.

Enhanced production of hydrogen via catalytic methane decomposition on a Pt7-Ni (110) substrate: a reactive molecular dynamics investigation

Abstract Numerous researchers in the energy field are engaged in a competitive race to advance hydrogen as a clean and environmentally friendly fuel. Studies have been conducted on the different aspects of hydrogen, including its production, storage, transportation and utilization. The catalytic methane decomposition technique for hydrogen production is an environmentally friendly process that avoids generating carbon dioxide gas, which contributes to the greenhouse effect. Catalysts play a crucial role in facilitating rapid, cost-effective and efficient production of hydrogen using this technique. In this study, reactive molecular dynamics simulations were employed to examine the impact of Pt7 cluster decoration on the surface of a Ni (110) catalyst, referred to as Pt7-Ni (110), on the rates of methane dissociation and molecular hydrogen production. The reactive force field was employed to model the atomic interactions that enabled the formation and dissociation of chemical bonds. Our reactive molecular dynamics simulations using the Pt7-Ni (110) catalyst revealed a notable decrease in the number of methane molecules, specifically ~11.89 molecules per picosecond. The rate was approximately four times higher than that of the simulation system utilizing a Ni (110) catalyst and approximately six times higher than that of the pure methane, no-catalyst system. The number of hydrogen molecules generated during a simulation period of 150 000 fs was greater on the Pt7-Ni (110) surface than in both the Ni (110) and pure methane systems. This was due to the presence of numerous dissociated hydrogen atoms on the Pt7-Ni (110) surface.

Recovery of cathode materials from waste lithium iron phosphate batteries through ultralow temperature treatment and mechanical separation

ABSTRACT Waste lithium iron phosphate (LFP) batteries consist of various of metallic and nonmetallic materials, with lithium being a critical strategic resource in the new energy era. Therefore, recycling LFP batteries has become a primary means of secondary lithium resource recovery. However, the presence of the strong binder polyvnylidene fluoride during the recycling process hinders the efficient recovery and separation of cell materials. This study proposes an innovative approach for recovery, involving ultralow temperature treatment and mechanical separation. In the experimental setup, the ultralow temperature treatment temperature at −140°C for 120 min, followed by 20 s of crushing, resulted in an impressive 96.5% dissociation rate of the cathode material and a purity of 94.2% for lithium iron phosphate. The physical and chemical changes in the cathode materials before and after ultralow temperature treatment were examined using differential scanning calorimetry, scanning electron microscopy, inductively coupled plasma optical emission spectrometer, X-ray fluorescence spectrometer, and X-ray diffraction (XRD). This method has the advantages of low cost, high efficiency, high environmental affinity and no additional products.

Moment Analysis Method for Measurement of Reaction Equilibrium and Rate Constants by Using High-Performance Liquid Chromatography.

The moment analysis method was developed for the determination of association equilibrium constant (KA) and association (ka) and dissociation (kd) rate constants of intermolecular interactions between solute and ligand molecules. They are accurately determined by using moment equations from elution peak profiles because they are measured by using high-performance liquid chromatography (HPLC) under preferable conditions that neither immobilization nor chemical modification (i.e., fluorescence labeling) of solute and ligand molecules is required. To demonstrate the effectiveness of the method, it was applied to the inclusion complex formation system between dibenzo-18-crown-6 (DB18C6) and alkaline earth metal cations, i.e., Mg2+, Ca2+, and Sr2+, as a concrete example. Because the diameter of the three metal cations is smaller than that of the inner cavity of DB18C6, the values of KA, ka, and kd were analytically determined by assuming the stoichiometry of 1:1 between DB18C6 and the metal cation. They reflected the influence of the difference in the size between the inner cavity of DB18C6 and the metal cations on the inclusion complex formation. It seems that the moment analysis method based on HPLC separation is effective for the multifaceted analysis of chemical reactions because some characteristics of the method are different from those of other conventional methods. It must contribute to the dissemination of an opportunity for the study of chemical reactions to many researchers because of the versatility of HPLC.

Theoretical Study on Ethylamine Dissociation Reactions Using VRC-VTST and SS-QRRK Methods.

Barrierless bond dissociation reactions play an important role in fuel combustion. In this work, the pressure-dependent dissociation rate constants of ethylamine (EA) are accurately determined using variable-reaction-coordinate variational transition-state theory combined with the system-specific quantum Rice-Ramsperger-Kassel method. Before the kinetics calculations, the performances of four density functional theory methods in describing the bond dissociation of EA are evaluated against the benchmark method, FIC-MRCISD(T)+Q/cc-pVTZ, and the MN15-L/cc-pVTZ method is the best choice. By comparison of the Gibbs free energies and the rate constants for the bond dissociation reactions of EA, ethanol, and propane, the influence of functional groups on the reaction kinetics is discussed. The kinetics calculations show that the dissociation rate constants of EA are sensitive to pressure at low pressures and high temperatures, and the dominant channel is the reaction that yields C2H5 and NH2 radicals. A literature combustion model of EA is updated with our calculations, and the satisfactory agreement between the model predictions and reported ignition delay times of EA suggests the reliability of our calculations.

Predicting high performance optoelectronic attributes containing iso-indacenodithiophene-based photovoltaic materials for future solar cell technology

Enhancing photovoltaic materials with improved power conversion efficiency (PCE), conduction band, and electrochemical attributes for organic solar cell (OSC) applications is a forefront area of research. This study is centered on the simulating and computational characterization of iso-indacenodithiophen (iso-IDTIC)-based new molecules (AF01-AF10) to obtain optimal candidates for high-performance OSCs. The proposed molecules have excellent PCE (∼15.97 %), fill factor (54.67), and open-circuit voltage Voc = 1.41 V, better than previous reports. DFT simulations-based analysis, including TDM, FMO, MEP, DOS, Voc, reorganization energies of hole and electron, and charge transfer analysis, were employed to confirm and comprehend the photovoltaic properties of proposed molecules. Reduction in energy gap (2.30–2.50 eV), binding energy (0.28–0.29 eV), enhanced λmax (586–686 nm) with HOMO → LUMO (>96 %) charge transfer was examined as compared to R(2.54 eV, 608 nm). Moreover, higher excitation dissociation rate, TDM, HOMODonor-LUMOAcceptor blend study, and reorganizational energy for electron and hole results confirmed that proposed molecules are efficient photovoltaic candidates for future solar energy applications.

Abstract 1970 Site-Directed Mutagenesis of Phytoglobins Leads to Increased Oxygen Dissociation Rates

Abstract 1970 Site-Directed Mutagenesis of Phytoglobins Leads to Increased Oxygen Dissociation Rates